1. Field of the Invention
This invention relates to a medicinal aerosol formulation, and more particularly, to a medicinal aerosol formulation comprising a stabilizer comprising a water addition.
2. Description of the Related Art
Delivery of drugs to the lung by way of inhalation is an important means of treating a variety of conditions, including such common local conditions as bronchial asthma and chronic obstructive pulmonary disease and some systemic conditions, including hormone replacement, pain management, cystic fibrosis, etc. Steroids, β2 agonists, anticholinergic agents, non-steroidal antiinflammatory agents, proteins and polypeptides are among the drugs that are administered to the lung for such purposes. Such drugs are commonly administered to the lung in the form of an aerosol of particles of respirable size (less than about 10 μm in diameter). The aerosol formulation can be presented as a liquid or a dry powder. In order to assure proper particle size in a liquid aerosol, as a suspension, particles can be prepared in respirable size and then incorporated into the suspension formulation containing a propellant. Alternatively, formulations can be prepared in solution form in order to avoid the concern for proper particle size in the formulation. Solution formulations must nevertheless be dispensed in a manner that produces particles or droplets of respirable size.
Once prepared an aerosol formulation is filled into an aerosol canister equipped with a metered dose valve. In the hands of the patient the formulation is dispensed via an actuator adapted to direct the dose from the valve to the patient.
It is important that an aerosol formulation be stable such that the pressurized dose discharged from the metered dose valve is reproducible. Rapid creaming, settling, or flocculation after agitation are common sources of dose irreproducibility in suspension formulations. This is especially true where a binary aerosol formulation containing only medicament and propellant, e.g. 1,1,1,2-tetrafluoroethane, is employed or where such formulation contains small amounts of surfactant as well. Sticking of the valve also can cause dose irreproducibility. In order to overcome these problems aerosol formulations often contain surfactants, which serve as suspending aids to stabilize the suspension for a time sufficient to allow for reproducible dosing. Certain surfactants also function as lubricants to lubricate the valve to assure smooth actuation. Myriad materials are known and disclosed for use as dispersing aids in aerosol formulations. Suitability of materials, however, is dependent on the particular drug and the propellant or class of propellant used in the formulation.
It is sometimes difficult to dissolve sufficient quantities of conventional surfactants in hydrofluorocarbon (HFC) propellants such as HFC-134a and HFC-227. Cosolvents, such as ethanol, have been used to overcome this problem, as described in U.S. Pat. No. 5,225,183. An alternative approach that avoids cosolvents involves materials that are soluble in hydrofluorocarbon propellants and are said to be effective surfactants or dispersing aids in an aerosol formulation. Among such materials are certain fluorinated surfactants and certain polyethyoxysurfactants.
It is known in the art that the presence of water in conventional aerosol formulations often result in a number of potential problems, e.g. stability of the formulation, erratic dose delivery, and, in some cases free radical reactions in the propellant. Therefore, it has generally been accepted that these preparations should be maintained substantially free of water. The rigorous exclusion of atmospheric moisture during both the manufacture and storage of such formulations, referred to as “developed” or “nascent” formulation water, increases the difficulties of preparing satisfactory stable aerosols containing the drug and raises the overall cost of the final product, especially when a moisture barrier, e.g. foil pouching, is included as a secondary package.
An exception had been found for beclomethasone dipropionate monohydrate. It has been reported that a formulation of this particular medicament combined with an amount of water in addition to its water of hydration is stable. In this regard, reference is made to U.S. Pat. No. 5,695,744 (“NEALE”).
U.S. Pat. No. 5,695,744 (NEALE) relates to aerosol formulations for the administration of beclomethasone dipropionate monohydrate by inhalation, which comprises at least 0.015% by weight of water in addition to the water of crystallization associated with the monohydrate form of the medicament in order to preserve the solvate form of the drug as well its particle size properties. It is particularly claimed that the formulation must comprise at least 0.015% by weight of the formulation of water in addition to the water of crystallization associated with said monohydrate whereby said at least 0.015% water stabilizes the particle size of said beclomethasone dipropionate monohydrate particles. It is noted that other work by the NEALE in U.S. Pat. No. 5,833,950 [Aerosol formulations containing beclomethasone dipropionate-1, 1, 1, 2-tetrafluoroethane solvate] suggests that, for these beclomethasone dipropionate formulations to be stable in propellant fluids, notably—1,1,1,2-tetrafluoroethane, the medicament must be in fine crystalline solvate form, and preferably, that the formulations of the invention are substantially free of other potential solvating species such as chlorofluorocarbons, ethyl acetate, alkanes, ethers, alcohols and water. NEALE most importantly suggest that, in particular, the formulations of the solvate of the beclomethasone compound must be substantially free of water, for example containing less than 250 ppm, preferably less than 200 ppm, more preferably less than 100 ppm, for example less than 50 ppm water (U.S. Pat. No. 5,833,950, NEALE).
NEALE in these patents, discloses aerosol formulation technology for beclomethasone dipropionate monohydrate alone that substantially maintains intact the particular solvate form as well as its crystal shape, morphology, and other surface enegertic properties in the formulation. It is understood then that maintenance of the solvate form of the particulate medicament, together with its particle size properties, is the primary and only technically justifiable purpose of the NEALE patents.
What has not been appreciated, however, is that despite all efforts an amount of water develops in medicinal aerosol formulations during processing of such formulations which can not be eliminated and is always present (“developed” or “nascent” formulation water). Most surprising and unexpected is that such unstable formulations, containing nascent formulation water, can be and are stabilized by the presence of a concentration of water added in addition to the nascent or developed formulation water which stabilizes such medicament formulations.